CN111187248A - Preparation method of cyclohexane derivative maleate crystal form - Google Patents
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- CN111187248A CN111187248A CN201811352263.3A CN201811352263A CN111187248A CN 111187248 A CN111187248 A CN 111187248A CN 201811352263 A CN201811352263 A CN 201811352263A CN 111187248 A CN111187248 A CN 111187248A
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- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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Abstract
The invention relates to a cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ]) as shown in a formula I]Thiophen) -4 yl-1-piperazines]Ethyl radical]Cyclohexyl radical]The preparation method of the maleate crystal form of the (E) -N, N-dimethylurea is an anhydrous crystal form and is generated under the condition that the water activity is less than or equal to 0.6 solvent.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a salt crystal form of a cyclohexane derivative for treating diseases in the field of psychology.
Background
The inventor has disclosed in CN106518841A compound 1 having the structural formula of formula I, whose chemical name is N '- [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea the cyclohexane derivative represented by the structural formula of formula I, N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea, has D2/D3 antagonist effect and 5-hydroxytryptamine absorption inhibition effect, and has application prospects in fields related to mental diseases, especially anti-schizophrenia effect.
The inventor also finds that the maleate of the compound with the structure shown in the formula I has unique advantages in a plurality of salt groups in the subsequent development process, for example, experiments show that the pharmacokinetic properties of the maleate have small individual difference, stable treatment effect and extremely high development value on the pharmacy. However, in the salt forming process, the maleate shows polymorphism phenomena such as solvent compounds, hydrated crystal forms, anhydrous crystal forms and the like, and the polymorphism medicine has a plurality of problems in preparing a medicine form, such as poor stability of the hydrated crystal forms and risk of drug property formation of the solvated crystal forms. Therefore, the anhydrous crystal form has the advantages of stable and high quality, safe pharmacy and the like in the process of preparing the medicine; however, in the preparation of the polymorphic forms, the inventors have found that the anhydrous crystalline form of the maleate salt of the compound of formula I is greatly affected by water activity, and that control of water activity is required to prepare a highly pure anhydrous crystalline form.
Disclosure of Invention
Based on the existing maleate salt of the compound shown in the formula I, the inventor develops the anhydrous crystal form of the maleate salt of the compound shown in the formula I; the molar ratio of the compound of formula I to the maleate salt is 1: 1. The chemical structural formula of the maleate of the compound of the formula I is shown as a formula II,
specifically, the present invention provides the following scheme:
the invention provides a maleate anhydrous crystal form of cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea shown as a formula I.
In one embodiment, the anhydrous crystalline maleate form of the invention has an X-ray powder diffraction spectrum using CuK α radiation at 2 Θ angles showing diffraction peaks at least at 11.804 ° ± 0.2 °, 12.703 ° ± 0.2 °, 13.493 ° ± 0.2 °, 14.495 ° ± 0.2 °, 15.096 ° ± 0.2 °, 17.108 ° ± 0.2 °, 19.104 ° ± 0.2 °, 19.655 ° ± 0.2 °, 20.023 ° ± 0.2 °, 21.611 ° ± 0.2 ° and 24.088 ° ± 0.2 °, preferably at least at 11.804 ° ± 0.02 °, 12.703 ° ± 0.02 °, 13.493 ° ± 0.02 °, 14.495 ° ± 0.02 °, 5 ° ± 0.02 °, 17.108 ° ± 0.02 °, 19.104 ° ± 0.02 °, 20.023 ° ± 0.02 °, 21.611 °, 24.088 ° ± 0.02 °.
In one embodiment, the maleate salt of the invention also exhibits diffraction peaks at 2 θ values of 7.246 ° ± 0.2 °, 17.567 ° ± 0.2 °, 18.794 ° ± 0.2 °, 20.395 ° ± 0.2 °, 21.030 ° ± 0.2 °, 22.496 ° ± 0.2 °, 24.867 ° ± 0.2 ° and 26.412 ° ± 0.2 °; preferably, diffraction peaks also exist at 2 θ values of 7.246 ° ± 0.02 °, 17.567 ° ± 0.02 °, 18.794 ° ± 0.02 °, 20.395 ° ± 0.02 °, 21.030 ° ± 0.02 °, 22.496 ° ± 0.02 °, 24.867 ° ± 0.02 ° and 26.412 ° ± 0.02 °.
In one embodiment, the maleate salt of the invention also has diffraction peaks at 2 θ values of 11.045 ° ± 0.2 °, 22.997 ° ± 0.2 °, 25.336 ° ± 0.2 °, 27.786 ° ± 0.2 °, 28.292 ° ± 0.2 °, 28.914 ° ± 0.2 °, 29.804 ° ± 0.2 °, 30.770 ° ± 0.2 °, 31.628 ° ± 0.2 ° and 33.952 ° ± 0.2 °; preferably, diffraction peaks also exist at 2 θ values of 11.045 ° ± 0.02 °, 22.997 ° ± 0.02 °, 25.336 ° ± 0.02 °, 27.786 ° ± 0.02 °, 28.292 ° ± 0.02 °, 28.914 ° ± 0.02 °, 29.804 ° ± 0.02 °, 30.770 ° ± 0.02 °, 31.628 ° ± 0.02 ° and 33.952 ° ± 0.02 °.
In one embodiment, the maleate salt of the invention has an anhydrous crystalline form XRPD pattern as shown in figure 2A.
In one embodiment, the maleate salt of the invention has an endothermic peak at 191.8 ℃ in DSC analysis of the anhydrous crystalline form.
In one embodiment, a DSC profile of the maleate salt of the present invention in anhydrous form is shown in figure 2B.
In one embodiment, the maleate salt of the invention loses up to 0.41% weight at 150 ℃ in a TGA analysis of anhydrous crystalline form.
In one embodiment, a TGA profile of an anhydrous crystalline form of the maleate salt of the invention is shown in figure 2C.
In one embodiment, the anhydrous crystalline forms provide the corresponding spacing values at 2 θ in Table 1
Characteristic peak of (2).
Table 1 XRPD diffraction peak data for anhydrous crystalline form of maleate salt
The invention further discloses a preparation method of the anhydrous crystal form, which comprises the following steps:
the maleate of the cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea shown in the formula I is recrystallized in the solvent condition that the water activity is less than or equal to 0.6, so as to obtain the anhydrous crystal form of the maleate shown in the formula I. The anhydrous crystal form is the crystal form.
Wherein, the recrystallization can be performed by using a recrystallization method which is generally conventional in the field, and the method comprises the following steps: antisolvent addition method, slow volatilization method, slow cooling method, suspension stirring method, circulation heating and cooling method, gas-solid permeation method, gas-liquid diffusion method and high polymer induction method. Preferably by suspension stirring.
Further, suspending the maleate of formula I in a solvent having a water activity of less than or equal to 0.6 to form a suspension; stirring the suspension for more than 12 hours at room temperature to reflux; the solid was collected to give form I above.
Further, the temperature of suspension is room temperature to 50 ℃.
The solvent is one or a mixture of alcohol, ketone, ester, ether, acetonitrile, substituted or unsubstituted hydrocarbon solvent, toluene and water, and the solvent is not limited in the invention as long as the water activity of the solvent in the crystallization process is less than or equal to 0.6. The alcohol is preferably ethanol, isopropanol or methanol; the ketone is preferably acetone or 2-butanone; the ethers are preferably methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran; the substituted or unsubstituted hydrocarbon solvent is preferably dichloromethane, n-heptane, n-hexane, cyclohexane.
The inventors have found at the time of their research that the interconversion relationship between the anhydrous and hydrate crystal forms was investigated by suspension competition tests in different water activities. The result shows that when the water activity is less than or equal to 0.6, an anhydrous crystal form is obtained, and when the water activity is more than or equal to 0.8, a hydrate crystal form is obtained.
Drawings
FIG. 1A is an X-ray powder diffraction pattern (XPRD pattern) of a crystalline form of the maleate salt of the compound of formula I in one embodiment of the present invention.
FIG. 1B is a Differential Scanning Calorimetry (DSC) plot of a crystalline form of the maleate salt of the compound of formula I in one embodiment of the present invention; the abscissa is temperature (. degree. C.); the ordinate is the heat flow (W/g); and thermogravimetric analysis (TGA profile).
FIG. 2A is an X-ray powder diffraction pattern (XPRD pattern) of the maleate salt anhydrous form of the compound of formula I in one embodiment of the present invention.
Figure 2B is a Differential Scanning Calorimetry (DSC) plot of the anhydrous crystalline form of the maleate salt of the compound of formula I in one embodiment of the present invention.
Figure 2C is a thermogravimetric analysis (TGA) of the anhydrous crystalline form of the maleate salt of the compound of formula I in one embodiment of the present invention.
Detailed Description
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.
The compound of formula I, the cyclohexane derivative of the compound of formula I, the N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea compounds expressed by the invention all refer to the same substance; the maleate of the compound of formula I, the maleate of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea and the compound of formula II are the same, namely the maleate of the compound of formula I, and the molar ratio of the maleate to the compound of formula II is 1: 1.
In the examples herein, temperature generally refers to room temperature (15-30 ℃).
Water activity generally refers to the measurement of the energy of water in the system, with higher water activity values leading to lower binding degrees; the lower the water activity value, the higher the degree of binding. The water activity Aw is defined as the ratio of the water vapor pressure P exhibited at a certain temperature to the pure water vapor pressure Po at the same temperature, i.e.: aw is P/Po. The invention is generally characterized by being detected by a Rotunic HP23-AW/SET40 portable water activity meter.
N' - [ trans-4- [2- [7- (benzo [ b ]) of the invention]Thiophen) -4 yl-1-piperazines]Ethyl radical]Cyclohexyl radical]X-ray powder diffraction pattern of the crystalline form of maleate salt of N, N-dimethylurea, expressed as diffraction peak position, i.e. diffraction angle 2 theta (°), interplanar spacing
Diffraction peak relative intensity (I/I0).
The term "relative intensity" refers to the ratio of the intensity of the other peak to the intensity of the peak having the highest intensity when the intensity of the peak having the highest intensity among all diffraction peaks of an X-ray powder diffraction pattern is 100%.
Examples
Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).
Amorphous forms of the compounds of formula I are prepared according to the methods reported in the prior art such as example 5 in CN106518841A, and are not limited thereto.
X-ray powder diffraction test parameters:
differential Scanning Calorimetry (DSC) characterization:
the measurement was carried out by using a Q2000/2500 differential scanning calorimeter of TA under the condition that the protective gas was nitrogen, the temperature rise rate was 10 ℃/min, and the temperature gradually increased from 25 ℃ to the set end point.
Thermogravimetric analysis (TGA):
the measurement was carried out by using a Q5000/5500 thermogravimetric analyzer manufactured by TA under the condition that the protective gas is nitrogen, the temperature rise rate is 10 ℃/min, and the temperature gradually rises from room temperature to a set terminal point.
Example 1: preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I)
Preparation of example 5 for free base reference CN 106518841A.
Preparation of 1-benzo [ b ] thiophene-4-piperazine hydrochloride
A mixture of 7.20g of 7-bromobenzo [ b ] thiophene, 19.9g of piperazine, 4.70g of sodium tert-butoxide, 0.32g of (R) - (+) -2,2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), 0.63g of dipalladium tris (dibenzylideneacetone) and 150ml of toluene was refluxed for 1 hour under a nitrogen atmosphere. 150ml of water was poured into the reaction solution, followed by extraction with 100ml of X3 ethyl acetate, washing with water, drying over anhydrous magnesium sulfate, and evaporation of the solvent under reduced pressure (0.01MPa, 45 ℃ C.). The residue was purified by silica gel column chromatography (dichloromethane: methanol: 25% aqueous ammonia 100:10:1) to obtain 4.60g of 1-benzo [ b ] thiophen-4-yl-piperazine as a yellow oil. 2ml of concentrated hydrochloric acid was added to a methanol solution (25ml) containing 4.6g of 1-benzo [ b ] thiophen-4-yl-piperazine and the solvent was evaporated under reduced pressure (0.01MPa, 45 ℃). To the residue was added ethyl acetate (50ml), and the precipitated crystals were filtered, dissolved in 15ml of methanol under reflux and then cooled to room temperature (25 ℃) to be recrystallized to obtain colorless needle-like crystals of 1-benzo [ b ] thiophen-4-yl-piperazine hydrochloride.
2.54g (10mmol) of 1-benzo [ b ] thiophene-4-piperazine hydrochloride and 2.40g (10mmol) of trans-2- {1- [4- (N-tert-butoxycarbonyl) amino ] cyclohexyl } -acetaldehyde are dissolved in 120ml of dichloromethane, 1.40ml (10mmol) of triethylamine are added at room temperature (25 ℃ C. + -2 ℃ C.) and stirred slowly for 10 minutes, then 3.16g (14.8mmol) of sodium triacetoxyborohydride are added stepwise, the reaction is stirred further at room temperature for 24 hours, and after the reaction has ended 120ml of a 10% sodium bicarbonate solution is added. The reaction system is directly extracted and separated, the organic phase is dried by anhydrous sodium sulfate, and finally filtered and evaporated to dryness, and the solid is refluxed, dissolved and cooled to room temperature (25 +/-2 ℃) by 15ml of ethyl acetate to obtain 3.70g of target product.
In an ice-water bath, 4.43g of trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl-carbamic acid tert-butyl ester was placed in a reaction flask, 80ml of an ethyl acetate solution of saturated hydrogen chloride was added, and a deprotection reaction was carried out by stirring for 8 hours to finally form a white precipitate, whereby 3.42g of the hydrochloride of the title compound was obtained. The solid was added to 50ml of a methylene chloride solution, 50ml of a saturated sodium bicarbonate solution was stirred for half an hour, followed by liquid-separation extraction, and the organic phase was concentrated (0.01MPa, 40 ℃ C.) to obtain 3.30g of the objective product.
Preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea
1.73g of trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexaneamine was dissolved in 50ml of dichloromethane, 1.40ml of triethylamine was added, followed by 5.50mmol of N, N-diformylcarbonyl chloride. Stirred at room temperature (25 ℃ C.. + -. 2 ℃ C.) for 48 hours. After the reaction, 50ml of water was added for extraction and separation, the organic phase was concentrated (0.01MPa, 45 ℃ C.), and the objective fraction was collected by column chromatography (400 mesh silica gel type) using 1:10 methanol in dichloromethane, and concentrated to obtain 1.89g of an amorphous objective product.
Example 2: preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I) maleate
The product from example 1, 200mg, was stirred with 1.05 molar maleic acid in 5ml Acetone (Acetone) to precipitate a solid, which was isolated as the maleate salt.
Example 3: preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea (compound of formula I) maleate hydrate crystal form
Salt 200mg in 5ml H as obtained in example 22And O, suspending and stirring for 3 days at room temperature, and centrifuging at room temperature to obtain the hydrated crystal form of the maleate of the compound in the formula I.
FIG. 1A shows the powder X-ray diffraction pattern (XRPD) peaks. The DSC results of figure 1B show that the sample has two endothermic peaks at 110.5 ℃ and 192.8 ℃; the TGA of figure 1B shows that the sample had a 5.64% weight loss when heated to 150 ℃.
Example 4: preparation of anhydrous crystalline form of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I) maleate
In a glass vial containing 15mg of the maleate obtained in example 2, 0.5mL of a mixed solvent of isopropyl alcohol and water (isopropyl alcohol/water: 0.98/0.02, Aw. about.0.2) was added, and after the resulting turbid liquid was magnetically stirred (1000rpm) at room temperature for 4 days, the solid was collected by centrifugation (10000rpm,2min) and subjected to XRPD test. Obtaining an anhydrous crystalline form of the maleate salt having an XRPD pattern as shown in figure 2A; in DSC analysis, there is an endothermic peak at 191.8 ℃ as shown in FIG. 2B, and in TGA analysis, the weight loss at 150 ℃ is 0.41% as shown in FIG. 2C.
Examples 5 to 19: n' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea (compound of formula I) maleate crystal form screening preparation
The crystalline form was prepared according to the method of example 4 using solvents of different water activities and the results are shown in table 2, wherein the obtained anhydrous form XRPD pattern was substantially the same as XRPD pattern 2A of example 4 and the hydrated form XRPD pattern was substantially the same as XRPD pattern 1A of example 3.
TABLE 2 Effect of Water Activity on the preparation of crystalline forms
Examples 20 to 23: n' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea (compound of formula I) maleate crystal form screening preparation
15mg of the maleate salt obtained in example 2 were weighed into a glass vial, 0.5mL of each of the listed solvents was added, and the resulting suspension was magnetically stirred (1000rpm) at 50 ℃ for a period of time, centrifuged (10000rpm,2min) to collect the solid and tested for XRPD. The results are shown in table 3, wherein the obtained anhydrous form XRPD pattern is substantially the same as XRPD pattern 2A of example 4 and the hydrated form XRPD pattern is substantially the same as XRPD pattern 1A of example 3.
TABLE 3 Effect of Water Activity on the preparation of crystalline forms
| Examples | Solvent(s) | Reaction time (sky) | Crystal form |
| Example 20 | Isopropanol (a)w～0) | 2 | Anhydrous crystal form |
| Example 21 | Methyl isobutyl ketone (a)w～0) | 2 | Anhydrous crystal form |
| Example 22 | Water (a)w～1) | 3 | Hydrated crystalline forms |
| Example 23 | DMSO/H2O(1:19，aw～0.9) | 1 | Hydrated crystalline forms |
Example 24: preparation of anhydrous crystalline form of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I) maleate
15mg of the maleate obtained in example 2 was taken in a 20mL vial, the solid was completely dissolved with 5.0mL of methanol, and to the clear solution was added dropwise methyl t-butyl ether as an antisolvent with stirring (1000rpm) until a solid precipitated. And separating the precipitated solid, and carrying out XRPD test to obtain an anhydrous crystal form. Wherein the obtained XRPD pattern of the anhydrous crystalline form is substantially the same as XRPD pattern 2A of example 4.
Example 25: preparation of anhydrous crystalline form of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethylurea (compound of formula I) maleate
15mg of the maleate salt obtained in example 2 was taken in a 3mL vial, dissolved by adding 1mL of methanol solvent, and the vial was sealed with a sealing film, and 4 pin holes were punched thereon, and left to slowly evaporate at room temperature. The resulting solid was collected and subjected to XRPD testing as an anhydrous crystalline form. Wherein the obtained XRPD pattern of the anhydrous crystalline form is substantially the same as XRPD pattern 2A of example 4.
Example 26: preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea (compound of formula I) maleate hydrate crystal form
15mg of the maleate salt obtained in example 2 was taken out into a 3mL vial, dissolved by adding a mixed solvent of 1mL of ethanol and 1mL of water, and the vial was sealed with a sealing film and pierced with 4 pinholes thereon and left to slowly evaporate at room temperature. The resulting solid was collected and subjected to XRPD testing as a hydrated crystalline form. The XRPD pattern of the hydrated crystalline form is substantially the same as XRPD pattern 1A in example 3.
Example 27: screening preparation of N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea (compound shown as formula I) maleate crystal form
And (4) adopting different solvent systems for slow cooling test. 15mg of each of the maleate salts obtained in example 2 was weighed into a 3-mL vial, 0.5mL of the solvent shown in Table 4 was added, and after stirring and equilibration at 50 ℃ for about 1 hour, the supernatant was filtered off. The obtained supernatant was placed in a biological incubator cooled from 50 ℃ to 5 ℃ at 0.1 ℃/min and kept at a constant temperature of 5 ℃, and the clear solution was transferred to a constant temperature of-20 ℃. The precipitated solid was collected and subjected to XRPD testing. The test results are shown in Table 4. Wherein the obtained anhydrous crystalline form XRPD pattern is substantially the same as XRPD pattern 2A of example 4 and the hydrated crystalline form XRPD pattern is substantially the same as XRPD pattern 1A of example 3. Wherein the obtained anhydrous crystalline form XRPD pattern is substantially the same as XRPD pattern 2A of example 4 and the hydrated crystalline form XRPD pattern is substantially the same as XRPD pattern 1A of example 3.
TABLE 4 Effect of Water Activity on preparing Crystal forms
| Examples | Solvent(s) | Crystal form |
| Example 27 | Ethanol (a)w～0) | Anhydrous crystal form |
| Example 28 | Acetonitrile (a)w～0) | Anhydrous crystal form |
| Example 29 | isopropanol/Water (4:1, a)w～0.95) | Hydrated crystalline forms |
Claims (10)
1. A method for preparing maleic acid salt anhydrous crystal form of cyclohexane derivative N' - [ trans-4- [2- [7- (benzo [ b ] thiophene) -4-yl-1-piperazine ] ethyl ] cyclohexyl ] -N, N-dimethyl urea in formula I is characterized in that recrystallization is carried out under the condition of solvent with water activity less than or equal to 0.6 to obtain the anhydrous crystal form of maleic acid salt in formula I.
2. The method of claim 1, wherein the recrystallization method comprises an antisolvent addition method, a slow volatilization method, a slow cooling method, a suspension stirring method, a cyclic temperature rise and drop method, a gas-solid permeation method, a gas-liquid diffusion method, and a high polymer induction method.
3. The method of claim 2, wherein the recrystallization process is a suspension agitation process.
4. The method of claim 3, wherein the recrystallization temperature is from room temperature to 50 ℃.
5. The method of claim 3, wherein the suspension stirring reaction time is greater than 12 hours.
6. The method of claim 1, wherein the solvent with water activity less than or equal to 0.6 is one of alcohol, ketone, ester, ether, acetonitrile, substituted or unsubstituted hydrocarbon solvent, toluene, water, or a mixture thereof.
7. The method of claim 6, wherein the alcohol is ethanol, isopropanol, methanol; the ketone is acetone or 2-butanone; the ethers are methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran; the substituted or unsubstituted hydrocarbon solvent is dichloromethane, n-heptane, n-hexane, cyclohexane.
8. The process according to claim 1, wherein the maleate of formula I is suspended in a solvent having a water activity of 0.6 or less to form a suspension, the suspension is stirred at room temperature to reflux for 12 to 96 hours, and the solid is collected by centrifugation to give the anhydrous crystalline form.
9. The method of any one of claims 1-8, wherein the anhydrous crystalline form has an X-ray powder diffraction spectrum according to fig. 2A.
10. The method of any one of claims 1 to 8, wherein the anhydrous crystalline form has a DSC profile as shown in figure 2B and a TGA profile as shown in figure 2C.
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| CN101878206A (en) * | 2007-10-23 | 2010-11-03 | 安蒂索马研究有限公司 | The crystal formation of (5,6-dimethyl-9-oxo-9H-xanthene-4-yl) acetic acid sodium salt |
| CN106518841A (en) * | 2015-09-15 | 2017-03-22 | 浙江京新药业股份有限公司 | Cyclohexane derivative or stereoisomer or salt and preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101878206A (en) * | 2007-10-23 | 2010-11-03 | 安蒂索马研究有限公司 | The crystal formation of (5,6-dimethyl-9-oxo-9H-xanthene-4-yl) acetic acid sodium salt |
| CN106518841A (en) * | 2015-09-15 | 2017-03-22 | 浙江京新药业股份有限公司 | Cyclohexane derivative or stereoisomer or salt and preparation and application thereof |
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